Synthesis of N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester and its regioselective radiofluorodestannylation to 6-[18 F]fluoro-L-dopa

ABSTRACT

A protected 6-trimethylstannyl dopa derivative has been synthesized for the as a precursor for the preparation of 6-[ 18  F]fluoro-L-dopa. The tin derivative readily reacts with electrophilic radiofluorinating agents such as [ 18  F]F 2 , [ 18  F]OF 2  and [ 18  F]AcOF. The [ 18  F]fluoro intermediate was easily hydrolyzed with HBr and the product 6-[ 18  F]fluoro-L-dopa was isolated after HPLC purification in a maximum radiochemical yield of 23%, ready for human use.

BACKGROUND

This invention was made in part with government support from aDepartment of Energy Grant DE-FC0387-ER60615, NIH Grant PO1-NS-15654 andNIMH Grant RO1-MH-37916.

The present invention relates to a high yield synthesis of atin-containing precursor for the preparation of fluorolabeled L-dopa andthe process for preparing that precursor and the labeled compound. Morespecifically, the invention relates to new alkyltin compounds(N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester and related compounds), its preparation and the productionof 6-[¹⁸ F]fluoro-L-dopa by reaction with three differentcyclotron-produced F-18 labeled fluorinating agents (F₂, acetylhypofluorite, and OF₂).

Several different methods have been disclosed in the literature forpreparing fluorine labeled L-dopa. However, they are all time consuming,require numerous processing steps to produce pure product and result inlow to modest yields.

The labeled L-dopa compound is radioactive and as a result has a limitedlifetime. Also, because of the radioactivity of the material, it isdesired that the handling and processing of the material be kept to aminimum and that the yield of the desired isomer be as high as possibleto eliminate the need to produce several batches of the 6- isomer tomeet daily laboratory needs.

Thus, there is a need for a shelf stable precursor. Further, there is aneed for a high yielding process which can be performed in a shortperiod of time.

SUMMARY

These needs are met by the present invention which comprises newalkyltin compounds(N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester and related compounds), its preparation, and the productionof 6-[¹⁸ F]fluoro-L-dopa by reaction with three different cyclotronproduced F-18 labeled fluorinating agents (F₂, acetyl hypofluorite, andOF₂).

More particularly the invention comprises the process of:

(1) forming N-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester byreacting 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride withsodium formate,

(2) reacting the product of step (1) with acyl hypoiodite to formN-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester,

(3) exposing the product of step (2) to BBr₃ to formN-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester,

(4) reacting the product of step (3) with di-t-butyl dicarbonate toproduce N-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethylester, and

(5) reacting the product of step (5) with hexamethylditin to formN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester.

6-[¹⁸ F]fluoro-L-dopa is prepared by bubbling [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂,or [¹⁸ F]OF₂ through the product of step 5 in organic solvent andtreating the resultant product with hydrobromic acid followed by partialneutralization with NaOH and purifying by preparative HPLC.

DRAWINGS

These and other features, aspects and advantages of the presentinvention will become better understood with reference to the followingdescription, appended claims, and accompanying drawing, where:

FIG. 1 is a representation of the steps performed to obtain the claimedtin compound and the fluorinated compound produced from the tincompound.

DESCRIPTION

Several neuropsychiatric diseases are believed to result fromalterations in the neurotransmitter systems such as the dopaminergicsystem. It has therefore become beneficial to characterize theintercerebral distribution and metabolism of biological materials whichnaturally occur in the brain and to evaluate the result of abnormallevels of these materials. A useful technique to perform thischaracterization is positron emission tomography (PET) with theassistance of a labeled material which can readily cross the blood-brainbarrier. Using this technique cholinergic, opiate and benzodiazepinereceptors have been studied in humans and living animals.

The dopamine system is the most widely studied neurotransmitter system.Dopamine deficiencies in the nigrostriatal system is a characteristic ofParkinson's disease and deficiencies or disturbances in dopaminemetabolism are believed to be responsible for Huntington's disease,schizophrenia and the effects caused by drug abuse (i.e., cocaine,amphetamines) as well as other locomotion and mood related problems. Amaterial found to be particularly useful for use in PET to characterizeand diagnose abnormalities in the dopaminergic system is 6-[¹⁸F]fluoro-L-dopa.

Both nucleophilic and electrophilic processes have been proposed for theproduction of labeled L-dopa. Nucleophilic synthesis requires amulti-step process with sensitive materials and is therefore difficultto perform on a routine basis. Electrophilic processes are generallypreferred because they are more amenable to routine production, are moreregioselective, and the resultant products are easily purified by singlepass preparative HPLC. Several electrophilic methods to prepare thismaterial have been used in the past. One method is based on the reactionof [¹⁸ F]acetyl hypofluorite with a partially blocked dopa derivative inacetic acid. The second method involves the reaction of L-dopa with [¹⁸F]F₂ in liquid HF. A third method reacts [¹⁸ F]acetyl hypofluorite witha fully derivatized dopa substrate to produce 2- and 6-fluorodopa inabout equal amounts. Fluorodemetallation methods involve use ofdopa-silane or dopa-mercury precursors. The first two processes producea mixture of three isomers and the third a mixture of two isomers whichmust be treated using time-consuming procedures to separate out the 6-isomer. Processes 1 and 2 have maximum yields of about 3%. Thedesilylation process produces the desired isomer in yields of only about8% but the preparation of the silane precursor is difficult and givesvery low yields. The fluoro-demercuration process can result in yieldsas high as 11%. The third process results in yields higher than thefirst two processes but lower than the desilylation process.

While the present invention comprises a multistep process, it is easy toperform, gives high yields for each step of the process and producesnew, shelf-stable alkyl tin compounds(N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester and related materials). This material can then react rapidlywith [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂, or [¹⁸ F]OF taken alone or in combinationto give high yields of 6-[¹⁸ F]fluoro-L-dopa which can be injected intoa patient and tracked by PET.

More particularly a process embodying features of the inventioncomprises the steps as shown in FIG. 1 of:

(1) reacting 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloridewith sodium formate to produce N-formyl-3,4-dimethoxy-L-phenylalanineethyl ester,

(2) forming N-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester byreacting the product of step one with acyl hypoiodite,

(3) mixing the product of step 2 with BBr₃ to formN-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester,

(4) reacting the product of step 3 with di-t-butyl dicarbonate toproduce N-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethylester, and

(5) reacting the product of step 4 with hexamethylditin to formN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester.

6-[¹⁸ F]fluoro-L-dopa is prepared by bubbling [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂,or [¹⁸ F]OF₂ through the product of step 5 and treating the resultantproduct with hydrobromic acid followed by partial neutralization withNaOH.

The formulation of the protected L-dopa derivative 1 by formicacid/acetic anhydride gave the N-formyl compound 2 in good yields. Theiodination of product 2 by acetyl hypoiodite, generated in situ, gaveexclusively the monoiodo derivative 3. While bromination has been foundto be suitable in the process of adding tin to simple molecules,bromination has been found to be unacceptable in the present reactionscheme and iodine has been found to be particularly facile. Thedimethoxy groups in 3 were hydrolyzed and then protected withtert-butoxycarbonyl (t-boc) groups. The t-boc protection of the catecholfacilitates fluoro-destannylation and also the final hydrolysis afterthe fluorination step. Moreover, the t-boc groups can easily bedeprotected with off-the-shelf HBr (48%) in less than 10 minutes whereasdimethoxy groups generally require HI (55%), distilled from redphosphorus under hydrogen, which is then stabilized with hypophophorusacid and stored in sealed ampules in the dark at low temperatures. Analternate to t-boc is acetoxy, alkoxy compounds or equivalent O-protecting groups.

Reaction of the iodo derivative 5 with hexamethylditin gave the ipsosubstituted tin precursor 6 as a room temperature shelf-stable andcrystalline white solid in good yields.

The fluorodestannylation of 6, unlike other fluorodemetallationreactions proceeded at an unexpectedly rapid rate and give unexpectedhigh yields. Compound 6 reacts with equal ease with the traditionalelectrophilic fluorinating agents such as fluorine and acetylhypofluorite as well as the recently rediscovered oxygen difluoride. Forinstance, both F₂ and OF₂ smoothly react with the tin precursor 6 togive the fluoro derivative 9 in isolated yields >65%.

The tin precursor 6 was also reacted with ¹⁸ F-labeled acetylhypofluorite, fluorine and oxygen difluoride. The ¹⁸ F-fluorointermediate 7 was readily hydrolyzed by HBr (48%) and the productpurified by preparative HPLC. The overall radiochemical yields obtainedwith [¹⁸ F]F₂ and [¹⁸ F]OF₂ by the present method are the highestheretofore achieved for the synthesis of 6-[¹⁸ F]fluorodopa. Since morethan a curie of [¹⁸ F]F₂ and [¹⁸ F]OF₂ mixture can easily be producedvia ¹⁸ O (p,n) ¹⁸ F reaction (Bida, G. T., Hendry, G. O., Bishop, A. J.and Satyamurthy, N. (1991) [F-18]F₂ Production via low energy protonirradiation of [0-18]O₂ plus F₂. Proceedings of the Fourth InternationalWorkshop on Targetry and Target Chemistry, Villigen PSI, Switzerland,Sep. 9-12, 1991; Bishop, A. J., Satyamurthy, N., Bida, G., Phelps, M. E.and Barrio, J. R. (1991) Spectroscopic identification and chemicalreactivity of the electrophilic F-18 species generated in the 0-18/F-18gas target system. J. Nucl. Med. 32, 1010), a routine and large scaleproduction (>100 mCi) of 6-[¹⁸ F]fluorodopa ready for injection is nowfeasible.

The Examples below set forth methods incorporating the invention forpreparing the tin precursor and the labeled L-dopa compound.

EXAMPLE 1 Preparation of the Tin Precursor

1. N-Formyl-3,4-dimethoxy-L-phenylalanine ethyl ester 2

To a mixture of 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride1 (Luxen, A., Perlmutter M., Bida, G. T., Van Moffaert, G., Cook, J. S.,Satyamurthy, N., Phelps, M. E. and Barrio, J. R. (1990) Remote,semiautomated production of 6-[¹⁸ F]fluoro-L-dopa for human studies withPET. Appl. Radiat. Isot. 41, 275) (5.3 g, 18.3 mmol) and sodium formate(1.44 g, 21.2 mmol) in formic acid (52 mL) cooled in an ice bath wasadded acetic anhydride (20 mL) and stirred at room temperature for 3 h.After addition of ethanol (40 mL) the mixture was stirred at roomtemperature for an additional 3 h and evaporated. The residue wasdissolved in ethyl acetate, filtered and the insoluble material waswashed with ethyl acetate. The combined filtrates were washedsuccessively with aqueous 10% HCl, saturated aqueous NaHCO₃ andsaturated aqueous NaCl. The organic extract was dried over anhydrousMgSO₄ and concentrated under reduced pressure to a yellow syrup.Crystallization of the syrup from ethyl acetate-petroleum ether give awhite solid 2 (3.1 g, 61%); m.p. 102°-103° C.

2. N-Formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester 3

Iodine (2.1 g, 8.3 mmol) was added to a solution of dimethoxy derivative2 (2.1 g, 7.5 mmol) and silver trifluoroacetate (2.0 g, 9.1 mmol) inmethylene chloride (110 mL) and the reaction mixture was stirred at roomtemperature for 48 h. The yellow precipitate that formed was filteredand washed with methylene chloride. The combined filtrates were washedwith 1M Na₂ S₂ O₅ (2×75 mL), water (2×75 mL), dried and concentratedunder reduced pressure to give a solid residue. Recrystallization ofthis residue from ethyl acetate and petroleum ether gave a white solid 3(2.3 g, 75%); m.p. 151°-152° C.

3. N-Formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester 4

To a solution of iodo derivative 3 (2 g, 4.9 mmol) in methylene chloride(35 mL) cooled in a -78° C. bath was added BBr₃ (17.5 mL of 1M solutionin methylene chloride) and the mixture was stirred at -78° C. for 15min. The cooling bath was removed and the stirring continued until themixture reached ambient temperature (˜30 min). Finally, the reactionmixture was poured into ice water (100 mL), stirred at room temperaturefor 30 min. and the methylene chloride layer was separated. Evaporationof methylene chloride under reduced pressure resulted in a pale yellowsolid 4 (1.2 g, 65%) m.p. 131°-132° C.

4. N-Formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethylester 5

A solution of di-t-butyl dicarbonate (1.41 g, 6.47 mmol) in anhydrousDMF (10 mL) was added dropwise to a solution of iodo derivative 4 (0.82g, 2.16 mmol) in anhydrous DMF (10 mL) and triethylamine (0.36 mL, 2.59mmol). After stirring the reaction mixture at room temperature for 16 h,ethyl acetate (75 mL) was added and the reaction mixture was washed withsaturated aqueous NaCl solution (3×50 mL) and water (3×50 mL).Evaporation of the organic phase after drying with anhydrous Na₂ SO₄gave a yellow syrup which was chromatographed over silica gel (ethylacetate-petroleum ether, 1:1) give a colorless oil 5 (1.02 g, 81%).

5.N-Formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester 6

Hexamethylditin (0.43 g, 1.31 mmol) was added to a mixture of iododerivative 5 (0.51 g, 0.88 mmol) and tetrakis-triphenylphosphinepalladium (0) (0.05 g) in anhydrous 1,4-dioxane (12 mL) and the reactionmixture was stirred under reflux in a nitrogen atmosphere for 6.5 h.After cooling, the black reaction mixture was filtered and the insolublematerial was washed with ethyl acetate. Evaporation of the combinedfiltrate gave a yellow oil which was chromatographed on silica gel(ether) to give a white solid 6 (0.35 g, 65%); m.p. 49°-50°.

EXAMPLE 2 Preparation of Unlabeled L-Dopa

1. N-Formyl-3,4-di-t-butoxycarbonyloxy-6-fluoro-L-phenylalanine ethylester 9

The electrophilic fluorinating agent, CH₃ COOF (prepared from 200 μmol)of F₂ in 1% He, (Bida, G. T., Satyamurthy, N. and Barrio, J. R. (1984)The synthesis of 2-[¹⁸ F]fluoro-2-deoxy-D-glucose using glycals: Areexamination. J. Nucl. Med. 25, 1327) F₂ (1% in He, 200 μmol) or OF₂(1% in He, 200 μmol), was bubbled into a solution of trimethyltinderivative 6 (0.123 g, 200 μmol) in Freon-11 (CFCl₃) (20 mL) at roomtemperature over a period of 30 min. The reaction mixture was dilutedwith methylene chloride (25 mL) and the organic phase was washed with 1MNa₂ S₂ O₅ (2×20 mL), water (2×20 mL) and dried (MgSO₄). Evaporation ofsolvents gave a yellow syrup which was chromatographed (silica gel,diethyl ether) to yield a colorless viscous oil 9 (41 mg, 43% in thecase of CH₃ COOF), (65 mg, 69% for F₂), (62 mg, 66% for OF₂).

2. 6-Fluoro-3,4-dihydroxy-L-phenylalanine (6-Fluoro-L-dopa) 10

N-Formyl-3,4-di-t-butoxycarbonyloxy-6-fluoro-L-phenylalanine ethyl ester9 (20 mg) was treated with 6.0N HCl (10 mL) and heated under reflux for5 h. Evaporation of HCl under vacuum gave 10 the hydrochloride as ayellow solid (10 mg, 94%).

EXAMPLE 3 Preparation of [¹⁸ F] Labeled L-Dopa 6-[¹⁸F]Fluoro-3,4-dihydroxy-L-phenylalanine 8

Radiolabeled [¹⁸ F]F₂ was produced via ²⁰ Ne (d,α) ¹⁸ F reaction in analuminum target body (Bida, et al., Ibid.). [¹⁸ F]Acetyl hypofluoritewas generated in the gas phase as reported in the literature (Bida, etal., Ibid.). Using ¹⁸ O(p, n) ¹⁸ F nuclear reaction, [¹⁸ F]F₂ [¹⁸F]oxygen difluoride mixture was produced in an aluminum target (Bishop,et al., Ibid.; Bida, et al., Ibid.).

The preparation of 6-[¹⁸ F]fluoro-L-dopa was carried out in a systemsimilar to that previously described for the remote, semiautomatedproduction of 6-[¹⁸ F]]fluoro-L-dopa (Luxen, et al., Ibid.). Theelectrophilic radiofluorinating agent, [¹⁸ F]CH₃ COOF prepared from 100μmol [¹⁸ F]F₂, [¹⁸ F]F₂ (100 μmol) or [¹⁸ F]OF₂ (100 μmol) was bubbledinto a solution of trimethyltin derivative 6 (61 mg, 101 μmol) inFreon-11 (CFCl₃ ; 10 mL) at room temperature over a period of 10 min.The solvent was evaporated at 50° C. with a gentle stream of nitrogenand the residue dissolved in methylene chloride (10 mL) and transferredto a chromatography column (0.7 cm i.d.) packed with Na₂ S₂ O₃ (2.5 cm)and silica gel (9.5 cm) that had been equilibrated with ether. Thecolumn was eluted initially with 5 mL of ether and this portion of theether solution was discarded. The radiolabeled intermediate 7 was theneluted with 25 mL of ether. The solvent was evaporated by bubblingnitrogen at 70° C. and the residue hydrolyzed with 48% HBr (2 mL) at130° C. for 10 min. After cooling to room temperature, the reactionmixture was partially neutralized with 3N NaOH (1.7 mL), diluted with1.3 mL of HPLC mobile phase (see below) and filtered (0.22 μm). Thesolution was injected onto an Alltech Adsorbosphere C-18 (7 μm) semiprepHPLC column (10×300 mm; solvent: 5 mM sodium acetate, 1 mM EDTA, 0.1%HOAc, 0.01% ascorbic acid; pH: 4; flow rate, 7 mL/min). The fractioncontaining 6-[¹⁸ F]fluoro-L-dopa 8, as monitored by a radioactivitydetector, was collected from the HPLC column, made isotonic with sodiumchloride and passed through a 0.22 μm membrane filter into a sterilemultidose vial. By analytical HPLC analysis (Waters μBondaPak C-18,0.46×30 cm column; eluent: 0.1% HOAc containing 3% methanol; flow rate,1 mL/min) the product, isolated by the semi-preparative HPLC, was foundto be >99% chemically (uv 282 nm) and radiochemically pure. Theenantiomeric purity of product 8 was confirmed by means of chiral HPLC(Chiral Pro=Si 100 Polyol (Serva) 4.6×250 mm; eluent: 50 mM KH₂ PO₄, 1mM CuSO₄ ; pH=4; flow rate, 1 mL/min) and found to be greater than 99%L-isomer, which suggests that no racemization occurs during thesynthesis process. The final product after decay of ¹⁸ F-isotope wasanalyzed by inductively coupled plasma spectrometry for organic andionic tin contamination and found to be <15 ppb total (detection limit:7 ppb). The overall synthesis took 60 min. for completion and theisolated radiochemical yields are given in Table 1. After the completedecay of ¹⁸ F (˜24 h), the product was also analyzed by ¹ H and ¹⁹ F NMRand the data were in agreement with those of the cold preparation asgiven above.

                  TABLE 1                                                         ______________________________________                                        Radiochemical yields for the production of                                    6-[.sup.18 F]fluoro-L-dopa from the aryltin precursor 6.                      [.sup.18 F]Radiofluorinating                                                                  Radiochemical yield*                                          agent           (%)                                                           ______________________________________                                        CH.sub.3 COOF    8                                                            OF.sub.2 (+F.sub.2)                                                                           18                                                            F.sub.2         23                                                            ______________________________________                                         *Theoretical maximum yield in all these reactions is 50%.                

The process of the invention sets forth a reliable and high yieldingprocedure for preparing a new shelf-stable aryltin compound which issuitable for reacting with labeled fluorine or fluorine compounds toproduce high yields (in excess of 20 percent) of very pure radiolabeled6-fluoro-L-dopa. The process of the invention also allows the direct useof radiolabeled fluorinating agents such as [¹⁸ F]F₂ and [¹⁸ F]OF₂ ; andthe efficient reactivity of the aryltin derivative 6 with variouscyclotron-produced radiofluorinating agents which is easily accessiblefrom a variety of nuclear reactions. The reproducible and highradiochemical yields permit a large scale production of 6-¹⁸F]fluorodopa with excellent chemical, radiochemical and enantiometricpurities useful for multiple PET studies.

The present invention has been described in considerable detail withreference to a certain preferred version and use thereof. However, otherversions and uses are possible. One skilled in the art will recognizethat, along with appropriate changes in the process, the chemicalsreferred to above can be replaced by other chemicals in the same family.For example, the electron withdrawing group on the 3 and 4 position onthe ring can be replaced by other electron with-drawing groups orcombinations of groups, such as methoxy, acetoxy or high molecularweight groups, the limiting factor being that the appended groups mustbe reducible to --OH in the final step of the process (methoxy is lesseffective than acetoxy or butoxy). Ethyl can be replaced by other alkylgroups such as methyl, butyl, or propyl; subject to limitations setforth above, one halogen can be replaced by other halogens; formyl canbe replaced by other acyl groups such as acetyl; and the alkyl group inhexamethylditin can be replaced by other alkyl groups or combination ofalkyl groups such as hexaethyltin. Therefore, the spirit and scope ofthe appended claims should not be limited to the description of thepreferred versions contained herein.

What is claimed is: 1.N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester.
 2. The process for producingN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester comprising:(a) formingN-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester by reacting3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride with sodiumformate, (b) reacting the product of step a) above with iodine andsilver trifluoroacetate to formN-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester, (c) exposingthe product of step b) above to BBr₃ to formN-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester, (d) reactingthe product of step c) above with di-t-butyl dicarbonate to produceN-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethyl ester,and (e) reacting the product of step d) above with hexamethylditin toproduceN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester.
 3. The process of claim 2 wherein the reactants in step a)are mixed with a cooled solution of formic acid and acetic anhydridefollowed by the addition of ethanol.
 4. The process of claim 2 whereinstep c) is initially conducted at -78° C. and the reaction mixture isthen allowed to reach ambient temperature.
 5. The process of claim 2wherein the di-t-butyl dicarbonate is added in a drop wise manner to theproduct of step c) dissolved in anhydrous dimethylformamide andtriethylamine.
 6. The process of claim 2 wherein the hexamethylditin wasmixed with tetrakis-triphenylphosphine palladium in anhydrous1,4-dioxane before reacting with the product of step d).
 7. The processof forming unlabelled 6-fluoro-L-dopa and 6-[¹⁸ F]fluoro-L-dopacomprising:(a) bubbling an unlabelled or radiolabeled fluorine compoundselected from the group consisting of [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂, and [¹⁸F]OF₂ and combinations thereof throughN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester, (b) treating the product of step a) above with hydrobromicacid, and (c) raising the pH of the product of step b) above to a value≦7 by the addition of NaOH.
 8. The process of forming unlabelled6-fluoro-L-dopa and 6-[¹⁸ F]fluoro-L-dopa comprising:(a) formingN-formyl-3,4-dimethoxy-L-phenylalanine ethyl ester by reacting3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride with sodiumformate, (b) reacting the product of step a) above with iodine andsilver trifluoroacetate to formN-formyl-3,4-dimethoxy-6-iodo-L-phenylalanine ethyl ester, (c) exposingthe product of step b) above to BBr₃ to formN-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester, (d) reactingthe product of step c) above with di-t-butyl dicarbonate to produceN-formyl-3,4-di-t-butoxycarbonyloxy-6-iodo-L-phenylalanine ethyl ester,and (e) reacting the product of step d) above with hexamethylditin toproduceN-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanineethyl ester, (f) bubbling an unlabelled or radiolabeled fluorinecompound selected from the group consisting of [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂,and [¹⁸ F]OF₂ and combinations thereof through the product of step e)above, (g) treating the product of step f) above with hydrobromic acid,and (h) raising the pH of the product of step c) above to a value ≦7 bythe addition of NaOH.
 9. The process for producing an aryltin precursorto be used in the formation of a fluorine labeled L-dopa compoundcomprising:(a) reacting 3,4-dialkoxy-L-phenylalanine alkylester-hydrochloride with a salt of an organic acid, (b) reacting theproduct of step a) above with an acyl hypoiodite, (c) exposing theproduct of step b) above to trihalogen boride, (d) reacting the productof step c) above with di-t-alkyl dicarbonate, and (e) reacting theproduct of step d) above with hexaalkylditin.
 10. The process of formingunlabelled as well as 6-[¹⁸ F]fluoro-L-dopa comprising:(a) reacting3,4-dialkoxy-L-phenylalanine alkyl ester-hydrochloride with a salt of anorganic acid, (b) reacting the product of step a) above with a halogen,(c) exposing the product of step b) above to trihalogen boride, (d)reacting the product of step c) above with di-t-alkyl dicarbonate, (e)reacting the product of step d) above with hexaalkylditin, (f) bubblingan unlabelled or radiolabeled fluorine compound selected from the groupconsisting of [¹⁸ F]CH₃ COOF, [¹⁸ F]F₂, and [¹⁸ F]OF₂ and combinationsthereof through the product of step e) above, (g) treating the productof step f) above with a halogen acid, and (h) raising the pH of theproduct of step g) above to a value ≦7 by the addition of a base.
 11. Acompound having the formula: ##STR1## Wherein: R₁ and R₂ are electronwithdrawing groups,R₃ is an amino acid, and R₄, R₅ and R₆ are alkylgroups.
 12. The compound of claim 11 where R₁ and R₂ are --O(CH₃)₃, R₃is ##STR2## and R₄, R₅ and R₆ are chosen from the group consisting of--CH₃ and --C₂ H₅.